Placebo – The Second Best Remedy: A Modern Perspective

Abstract
Although homoeopathy has employed placebos in practice since its inception, many physicians are still unaware and at times skeptical of the effects of placebos. This article seeks to reintroduce the Placebo to the modern homoeopath, educate him regarding its effects and understand how scientific community views placebos. This will also help in understanding the necessity of placebo controlled trials in the medical world.
Introduction
The use of placebo in prescription has been an indispensable part in clinical practice for almost every physician. It has been advised by Dr Hahnemann and advocated by other stalwarts too under special circumstances since the inception of homoeopathy. A close look at Hahnemann’s case journals reveals that the percentage for placebo prescriptions is very high. In his case journal no. 22 from 1821 85% of the medications are placebo. (1) This is also true in regard to his later years. In the period between 1833 and 1835 more than half (54%) of Dr Hahnemann’s prescriptions are placebo. (2) In most instances Dr Hahnemann marked placebos with the paragraph symbol (§). As observed in his case journals, the main reason for giving placebo by Dr. Hahnemann was to please the impatient patient who was used to frequent medications in allopathic medicine, not only every day but sometimes also hourly.
Studies on Dr Hahnemann’s case journals found that the founder of homoeopathy gave placebo to his patients also for other reasons as follows (3):
Hahnemann himself was not sure whether he had found the right homeopathic drug.
The patient looked so sensitive that he wanted to find out first how this patient would react to placebo.
If a female patient began to menstruate during the treatment, Hahnemann stopped the verum treatment and gave placebo.
If a patient was used to drinking tangy beer – which Hahnemann thought might have medicinal ingredients – this person was temporarily treated with placebos.
Since our medical practice utilizes the placebo regularly, it would be beneficial for us to learn what modern science has uncovered about its effects.
What is a Placebo?
According to Stedman’s Medical Dictionary (4), the word ‘placebo,’ which originates from Latin verb meaning ‘I shall please,’ has two meanings. First, a placebo may be an inert substance prescribed for its suggestive value. Second, it may be an inert substance identical in appearance with the compound being tested in experimental research, and the use of which may or may not be known by the physician or the patient; it is given to distinguish between the action of the compound and the suggestive effect of the compound under study. (5)
Currently, there is some disagreement as to the exact definition of a placebo. (6)
A broader definition of the placebo as given by Shapiro in 1961 is as follows: (7)
“Any therapeutic procedure (or that component of any therapeutic procedure) which is given deliberately to have an effect or unknowingly has an effect on a patient, symptom, syndrome, or disease, but which is objectively without specific activity for the condition being treated. The therapeutic procedure may be given with or without conscious knowledge that the procedure is a placebo, may be an active (non inert) or non active (inert) procedure, and includes, therefore, all medical procedures no matter how specific — oral and parenteral medication, topical preparations, inhalants, and mechanical, surgical and psychotherapeutic procedures. The placebo must be differentiated from the placebo effect, which may or may not occur and which may be favorable or unfavorable. The placebo effect is defined as the changes produced by placebos. The placebo is also used to describe an adequate control in research.”
A further refinement of the definition was proposed by Byerly (8) in 1976 as ‘any change in a patient’s symptoms that are the result of the therapeutic intent and not the specific physiochemical nature of a medical procedure.’
What is the Placebo effect?
There are four general reasons for clinical improvement in a patient’s condition:
(1) Natural history of the disease;
(2) Specific effects of the treatment;
(3) Regression to the mean; and
(4) Nonspecific effects of the treatment that are attributable to factors other than the specific active components.
The latter effect (4th one) is included under the heading ‘placebo effect’. (9) A beneficial response to an inert substance is a placebo response; a side effect to an inert substance is a nocebo response. (6)
Benedetti et al (2011) stated that a real placebo effect is a psychobiological phenomenon occurring in the patient’s brain after the administration of an inert substance, or of a sham physical treatment such as sham surgery, along with verbal suggestions (or any other cue) of clinical benefit. (10) Therefore, the effect that follows the administration of a placebo cannot be attributable to the inert substance alone, for saline solutions or sugar pills will never acquire therapeutic properties. Instead, the effect is because of the psychosocial context that surrounds the inert substance and the patient. (11)
Every time a physician recommends a diagnostic or therapeutic intervention for a patient, the possibility of a placebo effect forms a part of this clinical decision, that is, a clinical effect unrelated to the intervention itself may occur alongside the actual effects of the intervention. (12) Even more invasive procedures such as cardiac catheterization have been shown to have important associated placebo effects. (13)
Placebo effects are commonly observed in patients with cardiac disease as well who receive drug and surgical therapies as treatments. Rana et al. noted the ‘tremendous power of the placebo effect’ in patients with end-stage coronary disease in clinical trials of angiogenesis and laser myocardial revascularization. (14) They also commented on the fact that the observed improvements were not limited to ‘soft’ symptomatic endpoints but were also observed with ‘hard’ endpoints such as exercise walking time on a treadmill, and in magnetic resonance imaging. Rana et al. also studied the longevity of the placebo effect from published clinical trials. They found that the beneficial effects of placebo (on angina class, angina frequency, and exercise time) persisted for up to 2 years.
Similarly, another study by Mosely et al. (2002) showed that arthroscopic lavage with or without debridement is not better than and appears to be equivalent to a placebo procedure in improving knee pain and self-reported function. (15)
How does the placebo effect work? (Conceptual framework for understanding the placebo effect)
Many attempts have been made to conceptualize the placebo effect, including expectancy theory (Kirsch, 1985) (16), classical conditioning accounts (Wickramasekera, 1980) (17), context effects (Di Blasi et al., 2001) (18), and the meaning response (Moerman and Jonas, 2002) (19).
However, in a review (20), Colagiuri et al. (2017) adopted a framework proposed by Colloca and Miller’s (2011) (21) based on Integrative Framework Theory (Peirce, 1940) (22). Essentially, they propose that the placebo effect is a learned response, whereby various types of cues (verbal, conditioned, and social) trigger expectancies that generate placebo effects via the central nervous system. That is, they argue that while verbal, conditioned, and social cues differ in terms of their nature, these cues are integrated in order to generate central expectancies about treatment responses that drive the placebo effect. One advantage of this framework is that it allows integration of empirical findings for placebo effects established via verbal suggestion, direct and observational conditioning, and other social cues into a single conceptual model, rather than appealing to dual mechanisms.
Various types of learning phenomena that give rise to placebo effects as proposed by Colloca and Miller, 2011 (21) and Colloca, 2014 (23) are as follows:
Classical Conditioning: Numerous studies provide evidence that both pharmacological and non-pharmacological classical conditioning can lead to placebo effects. Amanzio and Benedetti (1999) (24) conducted one of the most interesting pharmacological conditioning studies.
Participants underwent two-days of conditioning with injections of either morphine (an opioid-based analgesic) or ketorolac (a non-steroidal anti-inflammatory analgesic).
On the placebo test day, participants were either given a saline injection or naloxone – an opioid antagonist – and were told that it was a painkiller.
Participants tested with saline showed significant placebo analgesia compared with a natural history group, irrespective of the type of drug that they were trained with. However, those given naloxone only demonstrated placebo analgesia if they had been conditioned with ketorolac and not with morphine.
Blockade of placebo analgesia by naloxone in the morphine group indicates that morphine-induced placebo analgesia involves the opioidergic system and is consistent with morphine’s pharmacodynamics.
Colloca and Benedetti (2006) (25) found that prior experience with an ineffective treatment attenuates the placebo effect. This attests to the importance of considering an individual’s prior experience with treatment, both positive and negative, in terms of predicting the likelihood of them experiencing a placebo effect.
Integrating verbal suggestion with conditioning: An important issue in placebo research has been trying to understand how verbal suggestion interacts with conditioning. As above, verbal suggestion may simply be considered to be one type of cue that can generate expectancies. One of the best examples of this is a study by Montgomery and Kirsch (1997) (26), who compared open placebo conditioning with surreptitious conditioning.
All participants received conditioning involving pairings of a placebo cream with a reduction in pain stimulation.
For one group the reductions were surreptitious i.e. not revealed, however for the other group they were open, with participants receiving (accurate) verbal suggestion that the researchers were reducing the pain stimulation when the cream was applied.
Despite both groups of participants receiving identical cream-pain reduction pairings, only the surreptitious group exhibited placebo analgesia on test.
The verbal suggestion that the pain stimulation was being reduced in the open group blocked placebo analgesia.
In this study, the verbal instructions in the open group perfectly predicted reduced pain during training, meaning that the placebo cream was a redundant cue to which no new expectancy learning occurred that would produce a placebo effect.
This type of finding indicates that individuals make use of all available cues – whether verbal or contextual – when learning what to expect from a treatment, which in turn influences the likelihood of them experiencing a placebo effect.
Are placebo effects always consciously mediated?: Three lines of evidence suggest that placebo effects may occur in the absence of conscious awareness.
First, counter-instructions following placebo conditioning, such as ‘this treatment is a placebo’, fail to completely eradicate the placebo effect (Schafer et al., 2015). (27)
Second, pharmacological conditioning of non-conscious processes, such as hormonal responses, appears capable of inducing placebo effects (Benedetti et al., 2003). (28)
Third, at least two studies suggest that conditioning with supposedly subliminal cues can lead to placebo analgesia and nocebo hyperalgesia (Jensen et al., 2012, Jensen et al., 2015). (29, 30)
However, conditioning without awareness has been a contentious issue. Lovibond and Shanks (2002) (31) critique of studies claiming learning without awareness may be particularly relevant for research on the placebo effect. They argue that most studies claiming learning without awareness involve much more sensitive tests of learning than of awareness, which according to them leads to false evidence of learning without awareness.
Social learning: All of the above examples of placebo effects involve direct first-hand experience. However, placebo effects can also be established via social learning. Colloca and Bendetti (2009) (32) were the first to demonstrate this.
They had participants observe a demonstrator reporting less pain when a placebo electrode was supposedly activated compared with when it was ‘inactive’. Participants were then exposed to the pain stimulation with and without the same placebo electrode being activated. Despite the intensity of the pain stimulation being equivalent, participants reported less pain with the placebo applied than without it. The fact that the participants never directly experienced pairings of the placebo with a reduction in pain indicates that their placebo analgesia was learned socially.
Notably, the magnitude of socially-driven placebo analgesic effects was comparable to conditioned responses and substantially larger than verbally-induced analgesia.
Recently, this evidence has been extended to video demonstrations, whereby viewing a video of an associate reporting less pain when a placebo is applied can also induce placebo analgesia in the observer (Hunter et al., 2014). (33)
Similarly, on the other hand studies have shown that nocebo effects can be established via social learning as well. (34) For example, many individuals report adverse effects as a results of exposure wind turbines, however evidence suggests that these effects are driven by negative expectancies induced by others’ reports of adverse effects, i.e. the nocebo effect, rather than any unconditioned adverse effects of the turbines. (35)
Additional studies have been attempted to both characterize and explore the mechanisms of the placebo effect. One such approach has been based upon the color and shape of pills and how that affects how patients feel about their medication. (6) For example, ScienceDaily (Jan. 19, 2011) (36) reported that according to recent research the color, shape, taste and even name of a tablet or pill may have an effect on how patients feel about their medication. (37)
A systematic review of 12 published studies of which six examined the perceived action of different colored drugs and six the influence of the color of a drug on its effectiveness was published by De Craen et al in 1996. (38) The studies on perceived action of drugs showed that red, yellow, and orange were associated with a stimulant effect, while blue and green were related to a tranquillizing effect. The analysis of the studies that assessed the impact of the color of drugs on their effectiveness showed inconsistent differences between colors. However, hypnotic, sedative, and anxiolytic drugs were more likely than antidepressants to be green, blue, or purple. Their overall conclusions were that colors affect the perceived action of a drug and may influence the effectiveness of some drugs, that a relation exists between the coloring of drugs that affect the central nervous system and the indications for which they are used, and that further research contributing to a better understanding of the effect of the color of drugs is warranted. (38)
Genetic influences on the placebo effect
Genetic variation is another important factor that may influence (and help predict) placebo effects. While the study of “the placebome”, or the genes that influence the placebo effect (Hall et al., 2015) (39), is only just emerging, its potential to improve our understanding of the mechanisms underlying the placebo effect is promising. The analysis of the genetic variants has centered around four systems, namely the dopamine, opioid, serotonin, and endocannabinoid systems. These systems have been found to influence cognitive and neural aspects of the placebo effect, and are seen as important pathways in the subjective experience of the symptom relief associated with the placebo effect (e.g. placebo analgesia). (20)
Doctors’ attitude towards placebo prescription
A systematic review found that estimates of the lifetime prevalence of prescribing pure placebos among doctors ranged from 17% to 80% (40) and it seems that doctors prescribe impure placebos more frequently than pure placebos. (41) (Pure placebos are substances or forms of treatment that have no pharmacological effect, e.g. sugar pills or saline infusions. Impure placebos have pharmacological effects, but the effect on the specific disease the substance is prescribed for has not been proven or is uncertain.)
Patient attitudes towards being prescribed placebo
Hull and colleagues surveyed adults in the USA to determine the acceptability of placebo treatments and found that most, but not all, respondents thought it was acceptable for doctors to use placebos under some circumstances. (42) However, although a significant number of patients (21.8% in the Hull et al. study) thought that placebos were not acceptable under any circumstances.
Findings of another study (43) suggest that people who find placebo-prescribing unacceptable do so because of beliefs that:
(i) Placebos are ineffective, which leads to the view that placebos are a waste of time and money, and pander to dependency on doctors and medications;
(ii) Placebos require deception, which leads to the view that a doctor who prescribes placebos is not to be trusted, and that patients’ involvement in their own healthcare is compromised; and
(iii) Patients that respond to placebos are gullible, foolish, or childish, leading to the view that they themselves would not want to be treated in this way.
On the other hand, people who find placebo-prescribing acceptable seem to do so primarily because they believe placebos can be effective and they prioritize such patient benefit over other concerns.
Placebo-Controlled Trials and Homoeopathy
Since its inception, there has been criticism against homoeopathy that it is nothing but a placebo and even in recent times it has been stated through trial that the beneficial effects are due to consultation process and not the remedy. (44) Although there are numerous studies which prove otherwise, due to poor methodological quality, these studies usually don’t make it into meta-analysis. Most studies do not follow homoeopathic principles properly (by using complex medicines or not following individualization) or do not provide sufficient time in a chronic case for the remedy to act. (45) According to Dr Vithoulkas, the homoeopathic principles to be taken into consideration when undertaking trials (46) are as follows:
Homeopathy does not treat diseases, but only diseased individuals. Therefore, every case may need a different remedy although the individuals may be suffering from the same pathology. This rule was violated by almost all the trials in most meta-analyses.
In the homeopathic treatment of serious chronic pathology, if the remedy is correct usually a strong initial aggravation takes place (47-49). Such an aggravation may last from a few hours to a few weeks and even then we may have a syndrome-shift and not the therapeutic results expected. If the measurements take place in the aggravation period, the outcome will be classified negative.
This factor was also ignored in most trials. (50) At least sufficient time should be given in the design of the trial, in order to account for the aggravation period. The contrary happened in a recent study (51), where the aggravation period was evaluated as a negative sign and the homeopathic group was pronounced worse than the placebo. (52)
In severe chronic conditions, the homeopath may need to correctly prescribe a series of remedies before the improvement is apparent. Such a second or third prescription should take place only after evaluating the effects of the previous remedies. (53) Again, this rule has also been ignored in most studies.
As the prognosis of a chronic condition and the length of time after which any amelioration set in may differ from one to another case (53), the treatment and the study-design respectively should take into consideration the length of time the disease was active and also the severity of the case.
In our experience, Homoeopathy has its best results in the beginning stages of chronic diseases, where it might be possible to prevent the further development of the chronic state and this is its most important contribution. Examples of pathologies to be included in such RCTs trials are ulcerative colitis, sinusitis, asthma, allergic conditions, eczema, gangrene rheumatoid arthritis as long as they are within the first six months of their appearance.
Dr Vithoulkas concludes his analysis by saying that the following points should be taken into consideration relating to trials that attempt to evaluate the effectiveness of homeopathy:
First, it is imperative that from the point of view of homeopathy, the above-mentioned principles should be discussed with expert homeopaths before researchers undertake the design of any homeopathic protocol.
Second, it would be helpful if medical journals invited more knowledgeable peer-reviewers who understand the principles of homeopathy.
Third, there is a need for at least one standardized protocol for clinical trials that will respect not only the state-of-the art parameters from conventional medicine but also the homeopathic principles. (54)
Fourth, experience so far has shown that the therapeutic results in homeopathy vary according to the expertise of the practitioner. Therefore, if the objective is to validate the homeopathic therapeutic modality, the organizers of the trial have to pick the best possible prescribers existing in the field.
Only when these points are transposed and put into practice, the trials will be respected and accepted by both homeopathic practitioners and conventional medicine and can be eligible for meta-analysis. (46)
Conclusion
The placebo effect is a well-recognized phenomenon in medical science which cannot be overlooked. Though many case reports do show the effectiveness of homoeopathic therapeutics, they do not account for possible placebo effects. Double-blind, Placebo-controlled Randomised Controlled Trials (RCTs) test true efficacy of any therapeutic means. To be able to produce good quality research in homoeopathy, we require first and foremost sound knowledge of application of the homoeopathic principles, some basic idea of research, the will, Patients and patience.
To help the policy makers to take decisions in favour of homoeopathy, the onus is on the practitioners and researchers to provide and publish good quality evidence which prove the efficacy of homoeopathy beyond placebo effect. Such trials will also help to assess the effectiveness of variations in practices and approaches adopted in homoeopathy, thus enriching the knowledge and evidence base in homoeopathy, thus ultimately benefitting the patient.
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